The ineffectiveness of the ordinary antihistaminic drugs in blocking the stimulating effect of histamine on gastric secretion has prompted the search for histaminic antagonists involved in this response. This effect of histamine, which is recognized as a powerful stimulator of gastric secretion, is communicated through H.sub.2 -receptors [Black et al., Nature 236, 385 (1972)] and is not inhibited by the classical antihistamines, H.sub.1 -receptor blockers [Ash and Schild, Brit. J. Pharmacol., 27, 427 (1966)]. Investigations in this direction culminated in the synthesis of a class of substances [G. J. Durant et al., J. Med. Chem. 20, 901 (1977)] typified by burimamide, the first clinically effective H.sub.2 -receptor antagonist. Although burimamide was sufficiently selective pharmacologically, it seemed to lack sufficient oral bioavailability. Metiamide, a subsequently evaluated H.sub.2 -antagonist, proved more potent and orally active in man than burimamide. However, metiamide could not be used in therapy due to its toxic side effects (agranulocytosis).
Cimetidine, a congener of metiamide bearing a cyanoguanidino group instead of a thioureido group, proved as potent as metiamide as an H.sub.2 -antagonist but was devoid of the toxic side effects of metiamide. Cimetidine has been recently used therapeutically as an anti-ulcer drug. Its half-life, however, is relatively short, and administration of several daily doses of 200 to 300 mg tablets is required. This shortcoming has prompted further research into the H.sub.2 -receptor blockers area aimed at finding longer acting and/or more potent substances. Recently, two new H.sub.2 -receptor antagonists--ranitidine (AH 19065) and tiotidine (lCl 125,225)--have been reported as possessing chemical features analogous to cimetidine, i.e., a linear methylthioethyl side-chain bearing neutral polar groups. The main chemical variation in the latter compounds with respect to cimetidine consists of the replacement of the imidazole by an aminoalkyl furan and a 2-guanidino-thiazole ring, respectively. Both ranitidine [Bradshaw et al., Brit. J. Pharmacol. 66 464 P (1979)] and tiotidine [T. O. Yellin, Life Sci., 25, 2001-2009 (1979)] have been reported to be more potent than cimetidine either as H.sub.2 -receptor antagonists during in vitro testing or as inhibitors of gastric acid secretion during in vivo testing.